1-196950869-T-C

Position:

• chr1-196950869-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005666.4(CFHR2):​c.271T>C​(p.Phe91Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CFHR2 NM_005666.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.602

Genes affected

CFHR2 (HGNC:4890): (complement factor H related 2) This gene belongs to a family of complement factor H-related genes (CFHR), which are clustered together with complement factor H gene on chromosome 1, and are involved in regulation of complement. Mutations in CFHR genes have been associated with dense deposit disease and atypical haemolytic-uraemic syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22497886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFHR2	NM_005666.4	c.271T>C	p.Phe91Leu	missense_variant	3/5	ENST00000367415.8	NP_005657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFHR2	ENST00000367415.8	c.271T>C	p.Phe91Leu	missense_variant	3/5	1	NM_005666.4	ENSP00000356385.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2024

The c.271T>C (p.F91L) alteration is located in exon 3 (coding exon 3) of the CFHR2 gene. This alteration results from a T to C substitution at nucleotide position 271, causing the phenylalanine (F) at amino acid position 91 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.049	.;T;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.65	T;T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.6	.;L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	.;D;.;.
REVEL	Benign	0.20
Sift	Benign	0.46	.;T;.;.
Sift4G	Benign	0.58	.;T;.;.
Polyphen		0.92	.;P;.;.
Vest4		0.090
MutPred		0.48		.;Gain of sheet (P = 0.0477);.;.;
MVP		0.71
MPC		0.022
ClinPred		0.61	D
GERP RS		2.8
Varity_R		0.10
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-196919999;